Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy

Abstract

Purpose: To investigate clinical and morphologic characteristics of serous retinal disturbances in patients taking extracellular signal-regulated kinase (ERK) inhibitors.

Design: Single-center retrospective study of prospectively collected data.

Participants: Of 61 patients receiving ERK inhibitors for treatment of metastatic cancer, this study included 40 eyes of 20 patients with evidence of retinopathy confirmed by OCT.

Methods: Clinical examination, fundus photography, and OCT were used to evaluate ERK inhibitor retinopathy. The morphologic features, distribution, and location of fluid foci were evaluated serially. Visual acuity (VA) and choroidal thickness measurements were compared at baseline, fluid accumulation, and resolution.

Main outcome measures: Characteristics of treatment-emergent choroid and retinal OCT abnormalities as compared with baseline OCT findings and the impact of toxicity on VA.

Results: Of 20 patients with retinopathy, most showed fluid foci that were bilateral (100%), multifocal in each eye (75%), and with at least 1 focus involving the fovea (95%). All subretinal fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. No statistical difference was found in choroidal thickness at fluid accumulation and resolution compared with baseline. Forty-five percent of eyes showed evidence of concomitant intraretinal edema localized to the outer nuclear layer. At the time of fluid accumulation, 57.5% eyes showed a decline in VA (mainly by 1-2 lines from baseline). For all eyes with follow-up, the subretinal fluid and intraretinal edema were reversible and resolved without medical intervention, and best-corrected VA at fluid resolution was not statistically different from baseline. Concomitant intraretinal fluid was not associated with worsening of VA. No patient discontinued or decreased drug dose because of retinopathy.

Conclusions: This study showed that ERK inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics. The observed foci were similar to mitogen-activated protein kinase kinase (MEK) inhibitor-associated retinopathy and distinct from central serous chorioretinopathy. However, unlike with MEK inhibitors, an increased occurrence of concomitant intraretinal fluid without significant additive visual impact seems to occur with ERK inhibitors. In this series, ERK inhibitors did not cause irreversible loss of vision or serious eye damage; retinopathy was self-limited and did not require medical intervention.

Keywords: Central serous chorioretinopathy; ERK inhibitor; MEK inhibitor; Retina; Subretinal fluid.

Figure 1:

Schematic diagram of 40 eyes of 20 patients showing the location, size and configuration of each fluid focus: blue = dome, green = caterpillar, red = wavy, yellow = splitting, grey = multifoil. Number represents patient number and circle designates those patients with visual symptoms. X at fovea designates the presence of intraretinal edema. Note the predominantly bilateral, multifocal involvement of the foci and relative symmetry between each eye.

Figure 2:

A representative case (patient 8) demonstrating fundus findings at time of fluid accumulation. Left column = right eye, right column = left eye. (A) Color fundus photograph showing placoid vitelliform lesions along the arcades and in the fovea corresponding to fluid foci. (B) These foci demonstrate hyper-autofluorescence. (C) Optical coherence tomography of macula demonstrating subretinal dome fluid with intraretinal edema in the outer nuclear layer. Note the absence of pigment epithelial detachments and hyperreflectile dots.

Figure 3:

Visual acuity changes at fluid accumulation and resolution. A) Waterfall plot demonstrating change in lines of Snellen visual acuity lines from baseline to fluid accumulation in 40 eyes. B) Waterfall plot demonstrating change in lines of Snellen visual acuity from baseline to fluid resolution in 22 eyes. No statistically significant difference was observed between baseline and at fluid resolution. * = eyes with intraretinal edema

Figure 4:

Two representative cases (patient 14 on right, patient 3 on left) demonstrating the “multifoil” configuration of subretinal fluid. Note the multiple undulations of the detached neurosensory retina simulating a multifoil arch.

Figure 5:

A representative case (patient 15) demonstrating optical coherence tomography findings at baseline, fluid accumulation and its resolution. Left column = right eye, right column = left eye. (A) Baseline optical coherence tomography showing normal retinal, retinal pigment epithelium (RPE) and choroidal structures. Note the difficulty in fully distinguishing the interdigitation zone (IZ) from the RPE and ellipsoid zone (EZ). (B) One day following first weekly dose of ERK-inhibitor fluid foci are detected in both eyes in dome configuration, fluid between RPE and IZ (“splitting”) with intraretinal edema in outer nuclear layer (ONL). (C) One week following first weekly dose, the fluid foci and intraretinal edema are resolving in both eyes. (D) One day after fourth weekly dose, the fluid foci and intraretinal edema have recurred. The IZ is elongated and both the IZ and EZ remain distinguishable and hyperreflectile. (E) One week following fourth weekly dose, the fluid foci and intraretinal edema are resolving in both eyes. (F) Two weeks after final sixth weekly dose, the retinal layers resume their normal appearance.